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The Influence of Age and Alzheimer’s Pathology on Hippocampal Function


An abundance of research has demonstrated that aging is associated with declines in cognition, particularly episodic memory. A similarly large body of work has highlighted the underlying age-related functional alterations that occur within the hippocampus and surrounding medial temporal lobes (MTL) that may give rise to memory impairment. However, aging is also associated with the accumulation of Alzheimer’s disease pathology, namely beta-amyloid plaques (Abeta) and tau neurofibrillary tangles, which have been associated with a host of neural and behavioral changes, even in those without the disease. As such, it is unclear to what extent our understanding of age-related decline is attributable to the accumulation of pathology. Using a combination of neuropsychological assessment, structural and functional magnetic resonance imaging, and positron emission tomography, I will present two projects which seek to quantify hippocampal function in cognitively normal older adults, assess how Abeta and tau interact to alter neural activity, and define a functional mechanism through which pathology leads to episodic memory decline.

The first project focuses on a function commonly attributed to the hippocampus called pattern separation. Here, using a lure discrimination memory paradigm, I demonstrate that cognitively normal older adults exhibit a behavioral shift from pattern separation towards pattern completion that is associated with elevated neural activity in the hippocampus and MTL. Additionally, I show that Abeta and tau are uniquely associated with two measures of neural function during memory encoding, suggesting that Abeta and tau pathology likely interact to produce aberrant neural activity in older adults. In the second project, I use a technique called representational similarity analysis to explore the relationship between memory encoding and retrieval. Here, I demonstrate that older adults exhibit greater neural similarity between encoding and retrieval for incorrect lures (i.e. false alarm) relative to correct lures. I also demonstrate that false alarm similarity is associated with tau, but only in older adults without Abeta. This suggests that, independent of Abeta, tau can disrupt memory function, specifically by altering the relationship between neural activity during encoding and retrieval. In sum, this research indicates that Alzheimer’s pathology alters hippocampal function in a way that leads to episodic memory impairment in cognitively normal older adults, and should be considered when addressing future questions about aging and memory.

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